Project 3 will test and clinically validate mechanisms and pharmacologic strategies explored in Projects 1-2, which target Akt-mTOR, AMPK-mTOR, and Fyn/RSK pathways. Advanced clinical/translational study of skin cancer carcinogenesis, biology, and pathophysiology will help reduce morbidity/ mortality, provide insight into keratinocyte signaling, and provide an easily-accessed human model of full-spectrum carcinogenesis for other epithelial cancers. The overall goal of this Program Project is to eradicate intraepithelial neoplasias (lEN) and substantially reduce the risk of squamous cell carcinoma. Our objectives are to determine clinical, histopathologic, karyometric, and protein/phosphoprotein activation patterns associated with human skin carcinogenesis and to develop safe, active drugs for skin cancer prevention. The hypothesis for this project is that topical small molecule drugs can modulate specific targets in solar UV-induced signaling cascades resulting in attenuation or reversal of skin sun damage. Aims include; 1) To demonstrate and cross-validate signaling targets and pathways activated in chronically sun-exposed human skin; 2) To validate signaling pathway modulation demonstrated by small molecule inhibitors in preclinical studies by acutely exposing human skin to solar simulated light; 3) To demonstrate safety and tolerability of new topical drugs when applied to human skin; 4) To demonstrate biomarker and epidermal target modulation by topical drugs applied to sun-damaged human skin; and 5) To demonstrate clinical benefit of topical drugs (especially drug combinations), and further validate biomarker selection in skin cancer chemoprevention trials. Developmental Aims include: 1) To further develop optical coherence tomography hardware and discriminative image-analysis software; and 2) To develop a